1. Field of the Invention
The present invention relates to a treatment of spinal muscular atrophy, and in particular relates to a treatment of spinal muscular atrophy using sodium-proton exchanger inhibitor.
2. Description of the Related Art
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of motor neurons in the anterior horn of a spinal cord, leading to muscular paralysis and atrophy. Clinically, according to the age of onset and its severity, SMA is traditionally categorized into three types with onset during childhood (type I, severe; type II, intermediate; type III, mild) and two additional types: one with adult onset of very mild symptom (type IV), and the other with prenatal onset of very severe symptom and early neonatal death (type 0) (Eur J Paediatr Neurol 1999; 3:49-51; Lancet 1995; 346:1162; Neuromuscul Disord 1992; 2:423-428). SMA occurs in approximately 1 in 6000-10000 live births and has a carrier frequency of 1 in 50. It is the second most common autosomal recessive inherited disorder in humans and the most common genetic cause of infant mortality (Semin Neurol 1998; 18:19-26).
SMA is caused by the homozygous deletion or mutations of the telomeric copy of the survival motor neuron gene (SMN1) on chromosome 5q13, which encodes the survival motor neuron (SMN) protein (Cell 1995; 80:155-165; Hum Mutat 2000; 15:228-237). A second centromeric copy of the SMN gene (SMN2) is also located at the same chromosomal region (Genomics 1996; 32:479-482). However, SMN2 expresses only limited amount of functional full-length SMN protein. A single nucleotide change (C to T) at the 6th position of exon 7 in SMN2 results in about 80% of SMN2 mRNA lacking exon 7, in comparison with the SMN1 mRNA that typically includes exon 7 (Hum Mol Genet 1999; 8:1177-1183; Proc Natl Acad Sci USA 1999; 96:6307-6311). The absence of exon 7 in SMN transcripts results in a defective SMN protein with reduced ability for self-oligomerization, leading to protein instability and degradation (Nat Genet 1998; 19:63-66). The SMN protein level in SMA patients is low and insufficient for normal functions in motor neurons (Hum Mol Genet 1997; 6:1205-1214; Nat Genet 1997; 16:265-269; Nat Genet 2000; 24:66-70). The C to T transition in the exon 7 of SMN2 is thought to disrupt an exonic splicing enhancer recognized by the serine/arginine-rich (SR) splicing factor SF2/ASF or create a novel splicing silencer site bound by hnRNP A1 (Nat Genet 2002; 30:377-384; Nat Genet 2003; 34:460-463).
The full-length SMN protein is ubiquitously expressed and localized to both the cytoplasm and nucleus. In the nucleus, the SMN protein appears concentrated in dot-like structures known as gems (Embo J 1996; 15:3555-3565). The SMN protein exists as a component of a multiprotein complex, which contains at least seven other proteins, named Gemins2-8, and plays an essential role in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) (Exp Cell Res 2004; 296:51-56; J Biol Chem 2006; 281:8126-8134). In addition, SMN may also have a neuron-specific function in an axonal transport of RNA (J Cell Biol 2003; 162:919-931; J Cell Biol 2003; 163:801-812).
There is no effective treatment to date for spinal muscular atrophy disease.